The present invention relates to the field of polymeric materials that can be used as implants (injectable or otherwise insertable) in mammals for hard and soft tissue augmentation.
A number of methods exist for plastic or reconstructive surgery using injectable implants. The implants have been used for cosmetic reasons, such as filling in dermal creases, and for medical reasons, such as in the treatment of urinary incontinence. Concerning urinary incontinence, this medical condition affects 10 million, mostly elderly, Americans at a cost conservatively estimated at more than $10 billion annually. Clearly, the commercial applications of a successful material or family of materials for tissue augmentation, including urinary incontinence, would be substantial.
An additional example of the potential for soft tissue is seen in the area of intervertebral disc repair. Each year in the U. S. low back pain results in productivity losses that are greater than for any other medical condition and results in health care costs of more than $33 billion. When disability and lost productivity are added, the economic losses exceed $100 billion per year. The common cause of low back pain is pathology of a soft tissue, the intervertebral disc. When disc degeneration occurs, a collapse of the disc space occurs, which leads to neuroforaminal narrowing and nerve impingement. Soft tissue restoration or repair of an injured intervertebral disc could theoretically occur at two levels. One level is to improve the outcome of a discectomy or laminectomy procedure by using materials to prevent the adhesions and fibrosis that result in failed back surgery syndrome. Another level is to use a material to regain the correct disc dimensions and viscoelastic properties and at the same time to provide for cellular attachment where cells can sense the forces that an approximately configured disc would sustain. To date, satisfactory materials for these purposes have not been developed.
Among the materials that have previously received serious consideration as periurethral bulking agents to combat urinary incontinence arising from such conditions as intrinsic sphincter deficiency (ISD) are a synthetic organic polymer, polytetrafluoroethylene (PTFE) (Blaivas and Jacobs, J. Urol. 145:1214-1218 (1991); Malizia, et al., JAMA 251:3277-3281 (1984)), autologous fat (Santarosa and Blaivas, J. Urol. 151:607-611 (1994)), sodium morrhuate (Murless, J. Obstet. Gynaecol. 45:67-73 (1938)), and paraffin (Quackels, Acta. Urol. Belg. 23:259-262 (1955)). While the initial use of PTFE indicated a 73% improvement rate for stress urinary incontinence (Blaivas and Jacobs (1991)), distant particle migration to the lungs, liver, spleen and brain was subsequently observed with formation of foreign body granulomas (Malizia, et al., supra). Other materials have been reviewed by Canning (Dial. Ped. Urol. 14 (1991)). Injectable bioglass has also been considered, but a 16- to 18-gauge needle appears to be required for injection, which results in tissue damage and leakage of the bioglass (Walker, et al., J. Urol. 148:645-647 (1992)).
Collagen, a natural component of connective tissue, has also been used for soft tissue augmentation (U.S. Pat. No. 5,428,022; Richardson, et al., Adult Urology, 46:378-381 (1995); Frank, et al., Plastic and Reconstructive Surgery 87:1080-1088 (1991); WO95/26761), as have polymer conjugates, such as polyethyleneglycol (U.S. Pat. No. 5,476,666). A glyceraldehyde cross-linked bovine dermal collagen with reduced antigenicity and increased resistance to fibroblast-secreted collagenases emerged as a promising material with about 80% of treated patients being either cured or improved after injection with this material (Richardson, et al. (1995); Stricker and Haylen, The Medical Journal of Australia, 158:89-91 (1993)). However, recent studies have shown that the cure rate is actually 25%, with 46% of the successful cases needing repeated injections within 3 years, i.e., a cure rate of 10-15% at the 3 year mark. Herschorn, et al., J. Urol. 156:1305-1309 (1996). In addition, up to 5% of patients exhibit a hypersensitivity reaction following the required intradermal skin test with this material (Siegle, et al., Arch. Dermatol. 120:183-187 (1984)), and are thus not suitable candidates for collagen therapy. The injection results in a mild inflammatory response in which the injected collagen attracts nearly equal amounts of host collagen over a period of about six months, resulting in permanent scarring (Stricker and Haylen (1993)). Such scarring can complicate further efforts at treatment. Furthermore, the material is completely degraded in 9 to 19 months, resulting in a need for repeated injections (Appell, The Craft of Urological Surgery 21(1):177-182 (1994)).
Artificial bioelastic polypeptides are a relatively new development that arose in the laboratories of the present inventor and are disclosed in a series of previously filed patents and patent applications. For example, U.S. Pat. No. 4,474,851 describes a number of tetrapeptide and pentapeptide repeating units that can be used to form a bioelastic polymer. Specific bioelastic polymers are also described in U.S. Pat. Nos. 4,132,746; 4,187,852; 4,589,882; and 4,870,055. U.S. Pat. No. 5,064,430 describes polynonapeptide bioelastomers. Bioelastic polymers are also disclosed in related patents directed to polymers containing peptide repeating units that are prepared for other purposes but which can also contain bioelastic segments in the final polymer: U.S. Pat. Nos. 4,605,413; 4,976,734; and 4,693,718, entitled xe2x80x9cStimulation of Chemotaxis by Chemotactic Peptidesxe2x80x9d; U.S. Pat. No. 4,898,926, entitled xe2x80x9cBioelastomer Containing Tetra/Pentapeptide Unitsxe2x80x9d; U.S. Pat. No. 4,783,523 entitled xe2x80x9cTemperature Correlated Force and Structure Development of Elastin Polytetrapeptidexe2x80x9d; U.S. Pat. No. 4,500,700, entitled xe2x80x9cElastomeric Composite Material Comprising a Polypeptidexe2x80x9d; U.S. Pat. No. 5,250,516 entitled xe2x80x9cBioelastomeric Materials Suitable for the Protection of Wound Repair Sitesxe2x80x9d; U.S. Pat. No. 5,527,610 entitled xe2x80x9cElastomeric Polypeptide Matrices for Preventing Adhesion of Biological Materialsxe2x80x9d; and U.S. Pat. No. 5,336,256 entitled xe2x80x9cElastomeric Polypeptides as Vascular Prosthetic Materialsxe2x80x9d.
A number of other bioelastic materials and methods for their use are described in pending U.S. patent applications, including: U.S. Ser. No. 08/316,802, filed Oct. 3, 1994, entitled xe2x80x9cBioelastomeric Drug Delivery Systemxe2x80x9d; U.S. Ser. No. 08/187,441, filed Jan. 24, 1994, entitled xe2x80x9cPhotoresponsive Polymersxe2x80x9d; U.S. Ser. No. 08/487,594, filed Jun. 7, 1995, entitled xe2x80x9cPolymers Responsive to Electrical Energyxe2x80x9d and published as PCT/US96/09776; U.S. Ser. No. 08/735,692, filed Oct. 16, 1995 entitled xe2x80x9cBioelastomers Suitable as Food Product Additivesxe2x80x9d and published as PCT/US96/05266; U.S. Ser. No. 08/542,051 filed Oct. 13, 1995, entitled xe2x80x9cHyperexpression of Bioelastic Polypeptidesxe2x80x9d; U.S. Ser. No. 08/543,020 filed Oct. 13, 1995, entitled xe2x80x9cA Simple Method for the Purification of a Bioelastic Polymerxe2x80x9d and published as PCT/US96/05186. All of the aforementioned patents and patent applications are herein incorporated by reference, as they describe in detail bioelastomers and/or components thereof and their preparation.
Artificial bioelastic materials are based on elastomeric and related polypeptides comprised of repeating peptide sequences (Urry, Angew. Chem. (German) 105:859-883 (1993); Angew. Chem. Omt. Ed. Engl. 32:819-841 (1993)). As a result of work conducted by the present inventor, the bioelastic polypeptides based on VPGVG have been found to be soluble in water below 25xc2x0 C., but on raising the temperature they associate reversibly to form a dense, water-containing viscoelastic phase in the polypentapeptide (xe2x80x9cPPPxe2x80x9d) and polytetrapeptide (xe2x80x9cPTPxe2x80x9d) cases, whereas the polyhexapeptide (xe2x80x9cPHPxe2x80x9d) associates irreversibly in water to form a granular precipitate, which usually requires the addition of trifluoroethanol to the aggregate for redissolution. The viscoelastic phase is called the coacervate, and the solution above the coacervate is referred to as the equilibrium solution. On cross-linking, the PPP and PTP polymers have been found to be elastomers, whereas the PHP polymer is not elastomeric and appears to provide a means for aligning and interlocking the chains during elastogenesis.
The process of raising the temperature to form the elastomeric state is an inverse temperature transition resulting in the development of a regular dynamic structure, unlike the random network structure of typical rubbers. The regular structure is a xcex2-spiral, a loose water-containing helical structure with xcex2-turns and spacers between turns of the helix which provides hydrophobic contacts between helical turns and has suspended peptide segments. These peptide segments are free to undergo large amplitude, low frequency rocking motions called librations. In addition, several of these xcex2-spirals associate to form twisted filaments. The elastomeric force of these various bioelastomers increases as the regular dynamic structure thereof develops. By synthesizing bioelastic materials having varying mole fraction amounts of the constituent repeating units and by choosing a particular solvent to support the initial viscoelastic phase, it is possible to rigorously control the temperature at which the obtained bioelastomer develops elastomeric force. Maximum elastomeric force develops over a relatively narrow temperature range at temperatures spanning a range of up to about 75xc2x0 C.
Bioelastic materials have been proposed for a number of uses and apparatuses, as indicated by the general subject matter of the applications and patents set forth above, and have been made available in different physical forms, such as sheets, gels, foams, or powders. For example, compositions can be used in medical applications ranging from the prevention of post-surgical adhesions (Urry, et al., xe2x80x9cBiotechnological Polymers: Medical, Pharmaceutical and Industrial Applicationsxe2x80x9d, pp. 82-103 (1993)) to programmed drug delivery. See also Urry, xe2x80x9cBioelastic Materials as Matrices for Tissue Reconstruction,xe2x80x9d in Tissue Engineering Current Perspectives, (Eugene Bell. Ed.), Birkhauser Boston, Div. Springer-Verlag, New York, N.Y., pp. 199-206 (1993). Materials functioning as insulator materials for isolating wound repair sites from adhesions, for the protection of burn areas, and to facilitate repair of the damaged tissue have been described in U.S. Pat. Nos. 5,250,516 and 5,527,610.
Despite the numerous techniques that have existed in the past for tissue augmentation, all of the existing techniques have suffered from one deficiency or another that have resulted in less than optimal results for the patient. There remains a need for biocompatible implants, especially injectable implants, for tissue augmentation, and the present invention provides compositions and methods for meeting those needs that do not suffer from the deficiencies of prior techniques.
It is an object of the invention to provide long-lasting implants for tissue augmentation or restoration.
It is also an object to provide implants that are injectable under a variety of surgical conditions, including emplacement during endoscopic surgery and related techniques.
It is a further object to provide for implants that match the compliance of the tissue site of application and that can be selected to match different compliance values with a minimum of difficulty.
It is yet another object to provide an implant that has both a carrier polymer that is biologically inert or at least degradable to non-toxic products, and a biologically active component.
It is another object of the invention to provide an implant that is readily sterilizable as well as being biocompatible, eliciting insignificant immunogenic and antigenic responses in the host.
It is a further object of the invention to provide an implant that, in biological situations involving implantation of exogenous material into a tissue, as in tissue regeneration or restoration, can stimulate cell adhesion and resulting cell growth upon appropriate modification or additions to the basic structure of the composition.
It is yet another object of the invention to provide a method for tissue augmentation, such as in plastic surgery (e.g., wrinkle removal) or to correct medical conditions (e.g., urinary incontinence or back pain resulting from degenerative defects in intervertebral discs).
These and other objects of the invention are achieved by providing a method for tissue augmentation in a warm-blooded animal comprising injecting a polymer at the tissue site in need of augmentation, which site has a tissue temperature, said polymer comprising repeating peptide monomeric units selected from the group consisting of nonapeptide, pentapeptide and tetrapeptide monomeric units, wherein said monomeric units form a series of xcex2-turns separated by dynamic bridging segments suspended between said xcex2-turns, wherein said polymer has an inverse temperature transition Tt less than said tissue temperature, and wherein said polymer is injected as a water solution at coacervate concentration in the substantial absence of additional water. The monomeric units can all be the same or they may be different. In specific embodiments, tissue reconstruction can be advantageously achieved using a polymer having the same elastic modulus of the natural tissue being augmented and, in some case, having the capability to induce natural cells of the tissue (or surrounding tissue) to enter and to function at the site of reconstruction.
Further objects of the invention are achieved by providing a method for tissue restoration of intervertebral discs in a mammal, said method comprising: injecting a polymer into the depleted nucleus pulposus site, which has a site temperature, said polymer comprising repeating peptide monomeric units selected from the group consisting of nonapeptide, pentapeptide and tetrapeptide monomeric units, wherein said monomeric units form a series of xcex2-turns separated by dynamic bridging segments suspended between said xcex2-turns, wherein said polymer has an inverse temperature transition Tt less than said site temperature, and wherein said polymer is injected as a water solution at coacervate concentration in the substantial absence of additional water and swells to increase the pressure within the disc.
The injectable protein-based polymers as taught herein can be designed to have numerous advantages including biological stability, biological function, and defined polymer size. These advantages are achieved by providing polymers composed of easily obtained and coupled monomer units, e.g. amino acids, that are themselves diverse in structure and in chemical properties and are readily modified. Furthermore, recombinant peptide-engineering techniques can be advantageously used to produce specific peptide backbones, either in bioelastic units or non-elastic biofunctional segments. Thus, the polymer can be present as a copolymer containing a mixture of tetrameric, pentameric or other monomeric units.
The polymers can be prepared with widely different water compositions, with a wide range of hydrophobicities, with almost any desired elastic modulus, and with a variable degree of cross-linking by selecting different amino acids for the different positions of the monomeric units and by varying the cross-linking process (e.g. chemical, enzymatic, or radiation) used to form the final product. Preparation of a variety of polymers that can be used in the present invention has already been described, for example in the publications discussed above, and the preparation of the polymers themselves is now established and not a novel part of the present invention, although the preparation of these materials as injectable formulations for use in tissue augmentation is new. Additionally, there are some preferred embodiments of polymers that can be prepared as described herein that are themselves new. For the most part, however, the invention involves the application of existing polymers (as well as new polymers) to a new field where they have not been used before.